The Scorpion King: Sword of Osiris is set after the events of The Scorpion King. The wizard Menthu and the witch Isis kidnap the hero Mathayus' sorceress bride Cassandra to use her powers to awaken the Dunes of Natash and unleash a thousand-year desert storm upon Egypt. To destroy the evil pair, Mathayus needs to uncover the world's most powerful blade, the Sword of Osiris, as well as the Hero's Gauntlet. After killing Menthu, Mathayus faces Isis, who uses the Scorpion Stone which transforms her into a half-scorpion monster for the final battle.
An alternate scenario depicts Mathayus kidnapped by the villains and it is Cassandra who fights to free him. If the player fails to defeat Isis, which happens if the player failed to collect all six runes, she flees with the Scorpion Stone.